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Single cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a pro-inflammatory metabolic signature in male mice at late adulthood (Part 2/2)

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Apr 24, 2024 version files 193.18 GB

Abstract

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants that bioaccumulate in the environment.  The gut microbiome is an important regulator of liver functions including xenobiotic biotransformation and immune regulation.  We recently showed that neonatal exposure to BDE-99, a human breast milk-enriched PBDE congener, up-regulated pro-inflammation- and down-regulated drug metabolism-related genes predominantly in males in young adulthood.  However, it remains unknown regarding the persistence of dysregulation into late adulthood, differential impact of hepatic cell types, and the involvement of the gut microbiome from neonatal BDE-99 exposure.  To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2-4.  At 15 months of age, neonatal BDE-99 exposure down-regulated key xenobiotic- and lipid metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes.  Neonatal BDE-99 exposure also persistently increased the hepatic proportion of neutrophils and led to a predicted increase of macrophage migration inhibitory factor signaling. This was associated with decreased intestinal tight junction protein (Tjp) transcripts, persistent dysbiosis, and dysregulation of inflammation-related metabolites.  ScRNA-seq using germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immunotolerance. Microbiota transplant to GF mice using large intestinal microbiome from adults neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in the large intestine.  In conclusion, neonatal BDE-99 exposure reprogrammed cell type-specific gene expression and communication in liver towards pro-inflammation, and BDE-99-mediated pro-inflammatory signatures may be partly due to the dysregulated gut environment.